Moving stem cell programs toward GMP manufacturing requires navigating a complex set of process dependent factors that influence identity, function, potency, and safety. Because outcomes are highly sensitive to even small changes in workflow, raw materials, or operator handling, teams routinely encounter obstacles in the transition from research environments to regulated manufacturing. In this discussion, three Landmark Bio experts share practical perspective on the most common challenges teams face: redesigning early stage processes for compliance, addressing operator driven variability, managing scale limitations, securing dependable raw materials, and aligning analytical methods with regulatory expectations. The conversation focuses on how thoughtful program design, structured execution frameworks, and early cross functional planning can improve reproducibility, reduce risk, and accelerate the path from development to clinic.
Speakers
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Process Development Scientist Landmark Bio |
Bioprocess Engineer Landmark Bio |
VP, Corporate Development & Licensing Landmark Bio |
James Cross Payne, Host (Cell & Gene): Stem cells offer powerful potential for regenerative medicine and next generation therapies, but their identity, potency, and safety are tightly tied to process conditions. Even small changes can introduce variability and risk as programs move toward GMP. In today's session, three experts from Landmark Bio will discuss key challenges in scaling stem cell programs, including research to GMP process redesign, operator variability, scaling limits, and regulatory alignment. Joining us are Kris Ward, VP of Corporate Development and Licensing; Ramiz Haddad, Bioprocess Engineer; and Meytal Haviv, Process Development Scientist. Together, they will provide practical strategies for process control, tech transfer, and early GMP planning to ensure reproducibility and reduce risk in stem cell programs. Welcome, Kris.
Kris Ward: Thank you, and welcome to our webinar, Translating Stem Cell Programs into GMP Manufacturing in the Clinic. Landmark Bio was founded as a translational CDMO to tackle the CMC and manufacturing challenges in advanced therapies. We were founded as a cross sector partnership between industry, research, hospitals, and academia from the Boston life sciences ecosystem.
Kris Ward: We were originally founded in 2019 by Harvard, MIT, Cytiva, Fujifilm, and Alexandria Real Estate, with additional founding collaborations with Mass General, Boston Children's, Dana-Farber, and Beth Israel. We then broke ground in the facility, which opened in 2022, where we hit the ground running with several projects commencing the very week we opened. In early 2025, we were also acquired by Artist Bio Solutions, which is something we're particularly excited about, as this has enabled us to continue to scale our operations and better support advanced therapies on their path to the clinic and commercialization.
Kris Ward: When I think about Landmark Bio, I like to think back to our founding mission. We are founded around CMC challenges at the translational stage, working to bring these programs to later stage clinical and commercial manufacturing. We are there to bring those perspectives to early development, to avoid CMC pitfalls and comparability issues down the line, while also providing a home for early development through commercial manufacturing. To accomplish this, the company was thoughtfully founded with drug development experts at the helm, coming from the drug development side of the industry with a proven track record in developing cell and gene therapies from early development through commercialization.
Kris Ward: Landmark Bio's mission is an important one for us. In our past positions, we have seen many good therapies fall by the wayside, not necessarily due to safety and efficacy as with traditional therapies, but because of CMC and comparability issues in advanced therapies. We founded Landmark Bio to solve that issue and bring these revolutionary treatments to patients.
Kris Ward: We have built a suite of service offerings to partner with drug developers based on our own experiences in drug development. We offer process development and analytical development services in addition to GMP manufacturing, including fill finish. We also offer CMC consulting and CMC regulatory support to support the entire continuum of preclinical development and translate these programs into the clinic. The idea is to have everything under one roof to support taking a process into the clinic and eventually commercialization.
Kris Ward: Our key differentiators come down to three things. First, collaboration. We work alongside our clients' staff to bring their biology and target expertise together with our bioprocessing expertise, and we encourage them to come into our labs and work alongside our team. Second, drug development expertise. We have walked in our clients' shoes, which allows us to be a partner and help collaboratively shape the CMC strategy rather than serve as a transactional vendor. Third, flexibility and agility. We have lived through early drug development ourselves and understand the fast paced nature of early CMC development and the need to pivot quickly as new data comes out.
Kris Ward: Our facility is in Watertown, just outside of Boston, Massachusetts. We have eight GMP processing suites, a fill finish suite, and our innovation and development lab where we house process and analytical development capabilities and supply preclinical material. We have also invested significantly in internal quality control capabilities and perform the majority of analytics in house wherever possible, given the importance of analytics both in process and at release for cell and gene therapies. Our proximity to some of the world's best clinical centers offers a unique opportunity, and we support fresh products in another facility, which is a testament to the team in QC and operations needing to be in lockstep to deliver those fresh products in and out of the facility. We also invested in digital infrastructure to connect data and systems across the facility. We reviewed the facility design with the FDA prior to breaking ground to ensure it was fit for purpose for clinical and commercial production.
Kris Ward: In terms of modalities we support, we wanted to build a comprehensive solution capable of handling as many operations as possible under one roof, including fill finish, so we can take things directly to drug product. Advanced therapies are getting more complex, with multiple technologies being combined into single therapies, and a diverse set of manufacturing capabilities is needed to handle that under one roof without creating an insurmountable amount of supply chain complexity. We support a broad range of cell therapies, including stem cell based programs such as HSCs, iPSCs, and others. We also support CAR-T, organoids, and cell printing. We support viral delivery with capabilities across lentiviral vector and AAV, including novel viral vector development and manufacturing. We have non viral delivery capabilities as well, supporting lipid nanoparticles, novel nanoparticles, extracellular vesicles, and other novel delivery technologies. We also have RNA and DNA capabilities, further strengthened by the recent announcement that Artist Bio Solutions is acquiring a synthetic DNA company, Sengoy, which will allow us to go from gene to drug all under one roof.
Kris Ward: Beyond familiar modalities, we also support novel modality development, which is an interesting part of what we do at Landmark Bio. For example, we have a great collaboration to support development of a novel organoid cell printing program, where the team works alongside us in our labs to create a knowledgeable, flexible, and agile team to tackle the CMC challenges inherent in novel modality development. With that, I will hand it over to Meytal to discuss translating stem cells to GMP.
Meytal Haviv: Stem cells, particularly iPSCs, offer significant therapeutic potential. They are pluripotent, renewable, and highly engineerable, enabling the generation of diverse therapeutic cell types and the support of complex cell and gene therapy platforms. At the same time, they are highly process dependent. Cell identity, potency, and safety are directly influenced by culture conditions and handling. Even minor variations in timing or process parameters can lead to meaningful differences in the final product. For this reason, robust process design and control are essential to ensure reproducibility and consistent clinical performance.
Meytal Haviv: When manufacturing falls short, the consequences are not theoretical. They directly impact regulatory timelines and patient access. Between 2020 and 2024, 74 percent of FDA complete response letters were driven by manufacturing or quality deficiencies. Nearly 40 percent of INDs are stopped or not accepted due to CMC deficiencies. The meaning is that many programs never even reach the clinic. When a clinical hold is issued for CMC reasons, it takes an average of 8.4 months to resolve, almost twice as long as protocol related issues.
Meytal Haviv: What drives those delays and holds? Common triggers include a weak potency assay, insufficient stability data, unresolved GMP or inspection findings, comparability gaps after process changes, release specification deficiencies, and lots that are not representative of clinical material. In short, many delays are not caused by the science. They are caused by process control, analytical readiness, and manufacturing strategy. Strong CMC development early on can prevent costly delays later. This is exactly why process control and CMC readiness are not regulatory hurdles. They are enablers.
Meytal Haviv: To prevent delays and clinical holds, risk must be addressed early, and that happens during process development. Process development is where we either build robustness into the process or allow risk to remain. Our role is to transform research protocols into workflows that are reproducible and GMP compatible.
Meytal Haviv: First, we build process and biology understanding. We identify biologically sensitive steps, define critical process parameters, and convert research use only protocols into robust, GMP ready workflows. iPSCs are highly sensitive to handling, timing, environmental conditions, and morphology. Morphology assessments can be very subjective, so we work to make handling, timing, and decision points more objective to reduce operator driven variability.
Meytal Haviv: Next, we define the scaling strategy aligned with the biology. We evaluate scale out versus scale up approaches and assess every vessel transition for potential risk, including shear forces, nutrient gradients, and impacts on differentiation fidelity, to ensure our workflow is scalable while preserving cell quality.
Meytal Haviv: We also establish materials and analytics early, selecting GMP compatible raw materials and developing assays that can transfer into manufacturing. The data generated in PD ultimately supports tech transfer and comparability, and the decisions made during process development directly define whether GMP manufacturing succeeds or struggles.
Meytal Haviv: For this MSC program, one of the main goals was to optimize both materials and vessels for GMP manufacturing, with the transition of research use only material to GMP compatible alternatives. For example, we sourced a premium Australian origin FBS that is heat inactivated and gamma irradiated instead of the common research use FBS. This ensures consistent lot quality, reduces the risk of xenogenic contamination, and supports regulatory documentation later on.
Meytal Haviv: We also selected pre coated vessels optimized for adherence, which removed variability from vessel coating, a critical process parameter, and reduced operator handling steps. Finally, we implemented consistent washes prior to fill finish and developed residual testing to confirm complete removal of media components, including the FBS and the cytokines. This step is essential for patient safety and compliance. It ensures all residual components are cleared before dosing and meets release requirements later, so it is not something done after the fact.
Ramiz Haddad: Now moving to technology transfer and translating PD into successful GMP execution. As Meytal touched on, manufacturing success is critical to minimizing clinical timeline creep and overall clinical success. How do you ensure that manufacturing success? Through intentional, structured technology transfer. That is what we do at Landmark, a fully structured technology transfer.
Ramiz Haddad: We perform full facility and process gap analyses, as well as product focused risk assessments, to identify risks early and implement mitigations at an early stage to minimize operational complexity. This is also where we go into full process design for GMP, including single use component design and process flow diagrams to communicate clearly. Within this step, we are fully collaborating with our PD partners and with manufacturing, QA, and QC. It is really a single unit operation. The output from these exercises supports cross functional and cross departmental responsibilities, and I want to highlight that cross departmental workflow.
Ramiz Haddad: On material and supply readiness, for GMP execution we have to qualify all of our new vendors and materials, finalize bills of materials, define preflight exercises, and coordinate on day of needs within process execution. Upon GMP execution, materials are released per a robust QA specification. Each material has a specification and is only used within the process upon release.
Ramiz Haddad: On operational execution and consistency, consistency is key, and we ensure consistency through robust on the job training. That includes classroom training, dry runs, and hands on training. We use our pilot and engineering runs to provide opportunities to iron out and ensure efficient execution of the process.
Ramiz Haddad: On analytical and CMC execution, we leverage engineering or client provided materials for assay verification, both for our in house assays and any new assays developed with the client. At the end of the day, we want to ensure regulatory aligned CMC from execution through release and onwards with our support.
Ramiz Haddad: Successful GMP execution depends on intentional process design and structured technology transfer. For our case study, we worked with a similar MSC process where there was a request to double our differentiation capacity to increase overall yield, going from four vessels to eight vessels. To do that, we worked with the client to understand the impact, because what looks like a simple change at the beginning has a spider web of impact throughout the process.
Ramiz Haddad: We took the approach of an in depth process review and identified several risks. The risks span extended manual processing, operational complexity, increased media volume to support the additional vessels, and upstream and downstream coupling. The transition between upstream and downstream has changes that, if not identified early, can impact overall yield.
Ramiz Haddad: Going through these risks, we not only identified them but also mitigated them. For extended manual processing, we saw a decrease in yield from centrifugation and manual manipulation of vessels, so we moved toward an automated harvest method, which reduced manual handling and increased viability and yield as the output of the process. Operational complexity brought about segmented manipulations and the need for additional biosafety cabinets and operators. To support the increase and minimize the time cells were out of optimal conditions, we implemented a two BSC process. This allowed us to split up the operations in a way that minimized product impact at the end of the day. The point is that scale up is not just a simple exercise. Every change has the potential to impact the process, and we want to understand that before we run, not hit those bottlenecks during execution.
Ramiz Haddad: We focus on a unit of collaboration, both internally and externally with our clients. There is a meaningful comparison between what is traditionally seen in the industry and how we approach it. Traditionally, process knowledge lives with PD and does not fully transfer to GMP. There is potential for gaps because of how the tech transfer is designed. Analytics develop in isolation, so assays are not GMP ready due to that lack of collaboration and communication. Each handoff is a risk, a point of failure where something can be missed.
Ramiz Haddad: In our model, handoffs happen within the same unit, so we are always co collaborating to bridge gaps at every point. When something goes wrong in GMP, traditionally the people who developed the process are not there. We ensure that the people who developed and transferred the process are on site and ready to assist with troubleshooting. With an integrated team, there are no translational gaps, analytics track to GMP timelines from day one, and risks surface early. Understanding the process gaps early in our case study allowed us to identify risks, mitigate them, and execute flawlessly. Unexpected things happen, and we want the right people there to make the right decisions for process success.
Ramiz Haddad: Integration does not eliminate complexity, but it means we are not surprised when complexity comes up.
Ramiz Haddad: Our stem cell process expertise spans from upstream through downstream: expansion, differentiation, and operator optimizations. We have experience with complex cell systems and provide end to end support under one roof, building on the under one roof model Kris described. That includes upstream and downstream workflow development, structured GMP tech transfer, and GMP manufacturing including fill finish. From cell banking to full GMP production, release, stability, CMC support, and IND enablement, we cover the full continuum.
Ramiz Haddad: On culture formats and scales, we have experience with iPSC programs from 2D to 3D and the transition between them, as well as different culture vessels. On analytics and product readiness, we have QC ready assays and assay development. We have in house qualified assays, and if a new or niche assay is needed, it can also be developed with our team. We support stability testing and logistics strategy as part of the program.
Ramiz Haddad: On seamless integration at any stage, we leverage our improvement platforms. If a client comes to us with a need that fits a platform we already have, we can adjust to client needs while building on proven approaches. If there is a more developed process, for example a GMP to GMP or PD to PD transfer, we integrate the client's process into our systems and execute per their expectations. For academic and early startup partners, we work in a joint innovation model, advising and consulting to understand their needs and co develop toward clinical success.
Ramiz Haddad: To summarize, Landmark Bio is comprised of experts from drug development backgrounds. We are flexible in supporting clients across PD, AD, and GMP manufacturing, as well as CMC support across the full range of modalities.
James Cross Payne: Thank you all very much for the excellent presentation. Our first question: how are programs structured as far as communication and working with clients?
Ramiz Haddad: For communication with our clients, right off the gate we have a project lead and project manager who serve as the key communicators and provide process expertise to communicate directly and effectively with the client. Beyond that, our different department heads serve as functional leads. Each department has a lead within the process, so for engineering and technology, for example, I would be the lead, and all responsibilities move through me and escalate up to the client. We also run joint sub team meetings, both internal and external, that support collaboration between the client and Landmark Bio. The goal is clear communication across the board.
James Cross Payne: What cell types have you worked with?
Meytal Haviv: The cell types we work with across our cell therapy processes at Landmark Bio are varied. We have iPSCs and MSCs, as well as experience with organoids. For every cell type we receive across different programs, the first thing we do is a lot of observation under microscopy, just to understand how the cells are growing, what they look like, when we need to do media changes, and when we need to passage. We monitor morphology and learn the specific requirements of the cells. That observation period is the key step before designing a robust process. The expert team we have here can handle every type of cell we have encountered.
James Cross Payne: What vessel formats have you used for this process to date, for example flasks, cell stacks, or bioreactors?
Meytal Haviv: We use a range of vessel types and sizes: T flasks, multi-layer cell stacks, pre coated vessels, spinner flasks, and PBS Mini bioreactors. We have a big diversity of vessels available. Based on the client request and requirement, we learn the morphology and understand the specific requirements of the cells, and then design the procedure to support that.
James Cross Payne: Are there any plans or constraints around changing vessel type as the process moves toward GMP?
Ramiz Haddad: Decisions to change vessel types usually happen early in the process, within process development. The goal is to design a robust workflow at the beginning so we can ensure reproducibility and quality as the process moves into GMP. Of course, any changes are addressed in the way we described in the case study, where we work with the client to identify risks and put mitigations in place.
James Cross Payne: What aspects of the process do you see as the highest risk when transferring into GMP manufacturing?
Ramiz Haddad: Cell therapy in general involves long, complex processes with complex media. One of the main challenges is keeping the process as closed as possible throughout, to maintain sterility and overall robustness. That involves how we handle media exchanges and cell manipulations, which are real risk points within the process. We implement careful controls to maintain sterility, and we leverage our expertise in single use design and process development to support overall process design.
James Cross Payne: That is all the time we have. Thank you to Kris, Ramiz, and Meytal from Landmark Bio for their expertise today, and to the audience for joining us.
Right from the start of a program, Landmark assigns a project lead and a project manager who serve as the primary communicators and provide process expertise across the engagement. Behind those two roles, each department has its own functional lead, so engineering and technology, process development, manufacturing, QA, and QC each have a clear point of contact. Responsibilities flow through these leads and escalate to the client as needed. Joint sub team meetings, both internal and client facing, keep collaboration tight. The goal is clear, structured communication across the board.
Landmark works with a range of cell types across cell therapy processes, including iPSCs, MSCs, and organoids, as well as HSCs and CAR-T programs. The team's approach with any new cell type starts with extensive observation under microscopy to understand how the cells grow, what they look like in culture, and when media changes and passaging are needed. Monitoring morphology and learning the specific requirements of each cell line is the foundational step before designing a robust process.
Landmark uses a wide range of vessel types and sizes, including T flasks, multi-layer cell stacks, pre coated vessels, spinner flasks, and PBS Mini bioreactors. The right vessel choice depends on the cell line, the client's requirements, and the morphology and growth characteristics observed during early process development. With the diversity of vessel formats available, the team can match the process design to what the cells actually need.
Decisions about vessel type are made early in process development. The goal is to design a robust workflow from the beginning, so reproducibility and quality carry through into GMP without late stage rework. If changes are needed, they are addressed through the same structured approach used elsewhere in the process: working with the client to identify risks, evaluate impact, and put mitigations in place before execution.
Cell therapy processes are long and complex and often involve complex media. One of the main challenges is keeping the process as closed as possible throughout, to maintain sterility and overall robustness. Media exchanges and cell manipulations are real risk points. The team addresses these risks through careful controls and by leveraging expertise in single use design and process development to build robust process architecture from the start.
Stem cells, particularly iPSCs, are pluripotent, renewable, and highly engineerable, which is what makes them powerful tools for therapy. That same sensitivity is what makes them process dependent. Cell identity, potency, and safety are directly influenced by culture conditions and handling. Even minor variations in timing or process parameters can lead to meaningful differences in the final product. That is why robust process design and control are essential for reproducibility and consistent clinical performance.
The numbers are striking. Between 2020 and 2024, 74 percent of FDA complete response letters were driven by manufacturing or quality deficiencies. Nearly 40 percent of INDs are stopped or not accepted due to CMC deficiencies, which means many programs never even reach the clinic. When a clinical hold is issued for CMC reasons, it takes an average of 8.4 months to resolve, almost twice as long as protocol related issues. Most of these delays are not caused by the underlying science. They are caused by gaps in process control, analytical readiness, and manufacturing strategy.
iPSCs are highly sensitive to handling, timing, environmental conditions, and morphology. Morphology assessments in particular can be subjective, which is one of the larger sources of operator driven variability. The team's approach is to make handling, timing, and decision points more objective during process development, so the steps that drive variability are tightened before they reach manufacturing. Where possible, automation is used to remove manual steps that contribute to variability, as in the differentiation case study where moving to an automated harvest method reduced manual handling and increased viability and yield.
Raw material qualification starts in process development by selecting GMP compatible alternatives to research grade materials. In the MSC case study, the team sourced premium Australian origin FBS that was heat inactivated and gamma irradiated, replacing the common research use FBS. That choice ensured consistent lot quality, reduced the risk of xenogenic contamination, and supported regulatory documentation later on. Pre coated vessels were used to remove variability in vessel coating, a critical process parameter, and to reduce operator handling steps. Residual testing was developed to confirm complete removal of media components, including FBS and cytokines, before fill finish, supporting both patient safety and release requirements.
A structured tech transfer starts with a full facility and process gap analysis and a product focused risk assessment, both done early enough to mitigate risk before it affects the timeline. From there, the team builds out full process design for GMP, including single use component designs and process flow diagrams. Material and supply readiness covers vendor qualification, finalization of bills of materials, and preflight coordination. Operational consistency is built through robust on the job training, including classroom, dry runs, and hands on practice, with pilot and engineering runs used to iron out the process before GMP execution. Analytics are verified using engineering or client provided materials, both for in house assays and any new assays developed with the client.
Scale up is rarely a simple change. In the MSC differentiation case study, doubling vessel count from four to eight surfaced risks across extended manual processing, operational complexity, increased media volume, and upstream and downstream coupling. The team's approach is an in depth process review to identify all of those risks before execution, then mitigate them deliberately. In that case, an automated harvest method reduced manual handling and increased yield, and a two BSC process split operations to keep cells from spending too long outside optimal conditions. Every change has the potential to ripple through the process. Understanding that ripple before running, not during, is what prevents bottlenecks.
In a traditional model, process knowledge lives with PD and does not fully transfer to GMP, analytics develop in isolation, and each handoff is a potential point of failure. When something goes wrong in GMP, the people who developed the process are usually no longer involved. Landmark's integrated model keeps handoffs within the same team, so collaboration bridges gaps at every point. Analytics track to GMP timelines from day one. Risks surface early. And when GMP runs encounter unexpected issues, the people who developed and transferred the process are on site to help troubleshoot. Integration does not eliminate complexity in stem cell programs, but it means the team is not surprised when complexity comes up.
Landmark supports stem cell programs end to end under one roof, from upstream through downstream: expansion, differentiation, and operator optimization. The team has experience with iPSC programs across 2D and 3D culture formats, and across various culture vessels. End to end support covers cell banking, full GMP production including fill finish, release and stability testing, CMC support, and IND enablement. On the analytical side, Landmark has in house qualified assays and the ability to develop new or niche assays as needed. The team also supports stability testing and logistics strategy as part of an integrated program.
Landmark engages clients three ways depending on program stage. For programs that match an existing platform, Landmark leverages improvement platforms that can be tailored to client needs. For programs with a more developed process, including GMP to GMP or PD to PD transfers, Landmark integrates the client's process into its systems and executes per client expectations. For academic and early stage startups, the team works in a joint innovation model, advising and consulting to understand client needs and co develop toward clinical success.